Phenethylacrylamide, methods for the production thereof and agents containing the same

ABSTRACT

The present invention relates to novel phenethylacrylamides of the formula I  
                 
 
in which the substituents R 1 , R 2 , R 3  and R 4  have the following meanings: 
         R 1  is hydrogen, halogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 3 -C 8 -cycloalkyl, C 1 -C 4 -haloalkoxy or C 1 -C 4 -haloalkyl;    R 2  is hydrogen, halogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 3 -C 10 -cycloalkyl, C 1 -C 4 -haloalkoxy or C 1 -C 4 -haloalkyl;    R 3  is C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, propargyl, C 3 -C 4 -alkenyl or a radical of the formula —H 2 C—C≡C—C(R a , R a )—R c , wherein R a , R b  independently of one another are hydrogen or methyl and R c  is hydrogen or C 1 -C 4 -alkyl;    R 4  is methyl or C 1 -haloalkyl; and Het is a 5- or 6-membered heteroaromatic ring, to processes for their preparation, and to the use of phenethylacrylamides of the formula I for controlling phytopathogenic harmful fungi.

The present invention relates to novel phenethylacrylamides, processesfor their preparation, and to the use of phenethylacrylamides forcontrolling phytopathogenic harmful fungi. Moreover, the inventionrelates to compositions for controlling phytopathogenic harmful fungiwhich comprise at least one phenethylacrylamide according to theinvention.

WO-A 96/17825 and WO-A 96/23763 disclose, inter alia, fungicidallyactive phenethylamides of α-oximinophenylacetic acid.

WO 01/95721 describes phenethylacrylamides of the formula

in which the substituents have the following meanings:

-   -   X is halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₈-alkoxy,        C₁-C₄-haloalkoxy and —O—C(R^(g),R^(h))—C≡C—R^(i), wherein        R^(g),R^(h) independently of one another are hydrogen and        C₁-C₆-alkyl and R^(i) is hydrogen, C₁-C₈-alkyl, C₃-C₈-cycloalkyl        and phenyl which can be substituted by halogen, cyano, nitro,        CF₃, C₁-C₄-alkyl and/or C₁-C₄-alkoxy;    -   Y is halogen, nitro, cyano, C₁-C₄-alkyl, CF₃, C₁-C₄-alkoxy and        phenyl;    -   k,l independently of one another are 1 to 4, it being possible        for the radicals X and Y to be different if k or l is greater        than 1;    -   R^(a), R^(b) independently of one another are hydrogen, halogen,        C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy and CF₃;    -   R^(c), R^(d), R^(e), R^(f) independently of one another are        hydrogen, C₁-C₄-alkyl and C₁-C₄-alkoxy or R^(c) and R^(d)        jointly form a cyclopropyl ring, it being possible for the        C—R^(e) and the C—R^(f) bonds to be in the E or Z position        relative to one another;    -   and their use for controlling phytopathogenic harmful fungi.

However, the fungicidal action of the compounds described in thedocuments mentioned above is frequently not satisfactory.

It is an object of the invention to find compounds with an improvedfungicidal action.

We have found that this object is achieved, surprisingly, byphenethylacrylamides of the formula I hereinbelow, which have aheterocyclic substituent in the a position relative to the carbonylgroup of the acrylamide unit. The present invention relates tophenethylacrylamides of the formula I

in which the substituents R¹, R², R³ and R⁴ have the following meanings:

-   -   R¹ is hydrogen, halogen, C₁-C₄-alkyl, C₁-C₄-alkoxy,        C₃-C₁₀-cycloalkyl, C₁-C₄-haloalkoxy or C₁-C₄-haloalkyl;    -   R² is hydrogen, halogen, C₁-C₄-alkyl, C₁-C₄-alkoxy,        C₃-C₁₀-cycloalkyl, C₁-C₄-haloalkoxy or C₁-C₄-haloalkyl;    -   R³ is C₁-C₄-alkyl, C₁-C₄-haloalkyl, propargyl, C₃-C₄-alkenyl or        a radical of the formula —H₂C—C≡C—C(R^(a), R^(b))—R^(c), where        R^(a), R^(b) independently of one another are hydrogen or methyl        and R^(c) is hydrogen or C₁-C₄-alkyl;    -   R⁴ is methyl or C₁-haloalkyl; and    -   Het is a 5- or 6-membered heteroaromatic ring which may contain        a fused 5- or 6-membered carbocycle and which is selected from        among heteroaromatic rings containing 1, 2, 3 or 4 nitrogen        atoms as ring members, heteroaromatic rings which contain 1 or 2        nitrogen atoms and 1 or 2 further heteroatoms selected from        among oxygen or sulfur as ring members, and heteroaromatic rings        which have 1 or 2 heteroatoms selected from among oxygen and        sulfur as ring members, Het being unsubstituted or it being        possible for Het to contain 1, 2 or 3 substituents S selected        from among halogen, C₁-C₄-alkyl, C₁-C₄-haloalkoxy,        C₁-C₄-haloalkyl and C₁-C₄-alkoxy.

The invention also relates to the use of the phenethylacrylamides of theformula I as fungicides, and to the crop protection compositionscomprising them.

Collective terms which generally represent the following substituentswere used in the definitions of the symbols given in the formulae of thepresent application:

-   -   halogen: fluorine, chlorine, bromine and iodine;    -   C₁-C₄-alkyl: saturated, straight-chain or branched hydrocarbon        radicals having 1 to 4 carbon atoms, for example methyl, ethyl,        propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl,        1,1-dimethylethyl;    -   C₃-C₁₀-cycloalkyl: a 3- to 10-membered, in particular 3- to        6-membered, cyclocaliphatic radical having 3 to 10, preferably 3        to 6, carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl, cycloheptyl and cyclooctyl, which radical can also        have attached to it 1, 2, 3 or 4 methyl groups, like in        methylcyclohexyl;    -   C₁-C₄-haloalkyl: straight-chain or branched alkyl groups having        1 to 4 carbon atoms (as mentioned above), it being possible for        some or all of the hydrogen atoms in these groups to be replaced        by halogen atoms as mentioned above, for example C₁-C₂-haloalkyl        such as chloromethyl, bromomethyl, dichloromethyl,        trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl,        chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl,        1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl,        2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl,        2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl,        2,2,2-trichloroethyl and pentafluoroethyl;    -   C₁-C₄-alkoxy: straight-chain or branched alkyl groups having 1        to 4 carbon atoms (as mentioned above) which are bonded to the        skeleton via an oxygen atom (—O—);    -   C₁-C₄-haloalkoxy: straight-chain or branched haloalkyl groups        having 1 to 4 carbon atoms (as mentioned above) which are bonded        to the skeleton via an oxygen atom (—O—);    -   C₃-C₄-alkenyl: alkenyl having 3 or 4 carbon atoms which is        preferably not bonded to an olefinic carbon atom, such as allyl,        methallyl and 2-buten-1-yl.    -   A 5- or 6-membered heteroaromatic ring is understood as meaning        an aromatic 5- or 6-membered ring which contains, as ring        members, one, two, three or four nitrogen atoms, 1 or 2 nitrogen        atoms and one or two further heteroatoms selected from among        oxygen and sulfur, or 1 or 2 heteroatoms selected from among        oxygen and sulfur, that is to say    -   aromatic 5-membered rings such as:        -   2-furyl, 3-furyl, 2-thienyl, 3-thienyl, pyrrol-2-yl,            pyrrol-1-yl, pyrrol-3-yl, pyrazol-1-yl, pyrazol-3-yl,            pyrazol-4-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl,            isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl,            imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, oxazol-2-yl,            oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl,            thiazol-5-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl,            1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl,            1,3,4-oxadiazol-2-yl, 1,2,3-thiadiazol-4-yl,            1,2,3-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl,            1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl,            1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl, tetrazol-5-yl,            1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, tetrazol-1-yl;    -   aromatic 6-membered rings such as:        -   pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazin-3-yl,            pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl,            pyrimidin-5-yl, pyrazin-2-yl, 1,3,5-triazin-2-yl,            1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl            or 1,2,4,5-tetrazin-3-yl;        -   it also being possible for Het to be a bicyclic ring system            which the abovementioned heterocycles can form together with            a fused 5- or 6-membered carbocycle, for example with a            phenyl ring or with a mono- or diunsaturated            C₅-C₆-carbocycle.

Het with a fused carbocycle is, for example, benzofuranyl, benzothienyl,indolyl, benzoxazolyl, benzothiazolyl, benzimidiazolyl, quinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl,5,6,7,8-tetrahydroisoquinoline or the like.

With a view to the fungicidal action of the phenethylacrylamides of theformula I, preferred compounds I are those in which R¹ and R² aredifferent and R¹ is a radical with a volume greater than that of R²,i.e. R¹ has a greater van-der-Waals radius than R² . Preferred amongthese are phenethylacrylamides I in which R² is hydrogen and R¹ is aradical other than hydrogen, preferably C₁-C₄-alkyl or C₃-C₅-cycloalkyl,in particular ethyl, isopropyl, tert-butyl or cyclopropyl.

Preferred compounds I are furthermore those in which R¹ and R² areidentical and are chlorine, fluorine or methyl.

Preferably, Het has at least one, in particular 1 or 2, substituents S.Preferred substituents on Het are: methyl, ethyl, isopropyl, methoxy,trifluoromethyl, difluoromethyl, fluorine, chlorine, bromine anddifluoromethoxy, in particular methyl, chlorine, bromine and CF₃. S ispreferably not bonded in the ortho position relative to the linkagesite.

Het is preferably C-bonded and is, in particular, an aromaticheterocycle which can be substituted in the above-described manner andwhich has, in particular, 1 or 2 substituents S, specifically thosesubstituents S which have been indicated as being preferred.

Het is, in particular, selected from among preferably mono- ordisubstituted:

-   -   aromatic 6-membered C-bonded heterocycles with 1 or 2 nitrogen        atoms such as pyridyl, pyrimidinyl or pyrazinyl, in particular        2-, 3- or 4-pyridyl, 4- or 5-pyrimidinyl and 2-pyrazinyl;    -   5-membered aromatic C-bonded heterocycles with one nitrogen atom        and one further heteroatom selected from among O, S and N, such        as pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl and        isothiazolyl, in particular 2-oxazolyl, 2- or 3-pyrazolyl; and    -   5-membered aromatic C-bonded heterocycles with one heteroatom        selected from among O, S and N, such as pyrrolyl, furanyl or        thienyl, in particular 3-furanyl or 3-thienyl.

Preferred with regard to the fungicidal action of thephenethylacrylamides of the formula I are, moreover, the followingmeanings of the substituens R¹, R², R³ and R⁴, in each case alone or, inparticular, in combination and, specifically, in combination with themeanings for Het and S which have been stated above as being preferred:

-   -   R¹ fluorine, chlorine, C₁-C₄-alkyl, C₁-C₄-alkoxy,        C₃-C₆-cycloalkyl and CF₃, in particular C₁-C₄-alkyl or        C₃-C₆-cycloalkyl, and specifically isopropyl, tert-butyl or        cyclopropyl;    -   R² hydrogen, fluorine, chlorine or methyl, in particular        hydrogen;    -   R³ methyl, ethyl, CF₃, CH₂CF₃, allyl, propargyl or        CH₂—C≡C—CH₂—(C₁-C₄-alkyl), in particular methyl, ethyl or        propargyl;    -   R⁴ methyl or CHF₂.

Especially preferred embodiments of the invention are thephenethylacrylamides of the formulae I.1 to I.3:

in which the substituents S, R¹, R², R³ and R⁴ have the abovementionedmeanings, in particular the meanings which have been mentioned above asbeing preferred, n is 1 or 2 and S is not bonded in the ortho positionrelative to the linkage site (i.e. in the 3 and/or 4 position relativeto the linkage site).

Likewise preferred are the compounds of the general formula I whereinHet is one of the radicals Het-4 to Het-8 given hereinbelow.Accordingly, these compounds are hereinbelow also referred to ascompounds I.4 to I.8.

In the formulae Het-4 to Het-8, S has the abovementioned meaning. Thevariable n is 0, 1 or 2, preferably 1, and the variable m is 0 or 1.

Especially preferred with regard to their use are the compounds Icompiled in the Tables 1 to 31 which follow. Moreover, the groupsmentioned in the tables for Het and S constitute an especially preferredembodiment of the compounds according to the invention, independently ofthe combination with the substituents R¹ to R⁴ in which they arementioned.

Table 1

Compounds of the formula I.1 with a 2-pyridyl radical in which (S)_(n)is 4-trifluoromethyl and wherein, for a given compound, R¹, R², R³ andR⁴ correspond to one line of Table A (compounds I.1a.1 to I.1a.81).

Table 2

Compounds of the formula I.1 with a 2-pyridyl radical in which (S)_(n)is 4-CH₃ and wherein, for a given compound, R¹, R², R³ and R⁴ correspondto one line of Table A (compounds I.1b.1 to I.1b.81).

Table 3

Compounds of the formula I.1 with a 2-pyridyl radical in which (S)n is4-OCH₃ and wherein, for a given compound, R¹, R², R³ and R⁴ correspondto one line of Table A (compounds I.1c.1 to I.1c.81).

Table 4

Compounds of the formula I.1 with a 2-pyridyl radical in which (S)n is4-Cl and wherein, for a given compound, R¹, R², R³ and R⁴ correspond toone line of Table A (compounds I.1d.1 to I.1d.81).

Table 5

Compounds of the formula I.1 with a 2-pyridyl radical in which (S)_(n)is 4-Br and wherein, for a given compound, R¹, R², R³ and R⁴ correspondto one line of Table A (compounds I.1e.1 to I.1e.81).

Table 6

Compounds of the formula I.1 with a 3-pyridyl radical in which (S)_(n)is 4-trifluoromethyl and wherein, for a given compound, R¹, R², R³ andR⁴ correspond to one line of Table A (compounds I.1f.1 to I.1f.81).

Table 7

Compounds of the formula I.1 with a 3-pyridyl radical in which (S)_(n)is 4-CH₃ and wherein, for a given compound, R¹, R², R³ and R⁴ correspondto one line of Table A (compounds I.1g.1 to I.1g.81).

Table 8

Compounds of the formula I.1 with a 3-pyridyl radical in which (S)_(n)is 4-OCH₃ and wherein, for a given compound, R¹, R², R³ and R⁴correspond to one line of Table A (compounds I.1h.1 to I.1h.81).

Table 9

Compounds of the formula I.1 with a 2-pyridyl radical in which (S)_(n)is 5-trifluoromethyl and wherein, for a given compound, R¹, R², R³ andR⁴ correspond to one line of Table A (compounds I.1i.1 to I.1i.81).

Table 10

Compounds of the formula I.1 with a 2-pyridyl radical in which (S)_(n)is 5-Cl and wherein, for a given compound, R¹, R², R³ and R⁴ correspondto one line of Table A (compounds I.1k.1 to I.1k.81).

Table 11

Compounds of the formula I.1 with a 2-pyridyl radical in which (S)_(n)is 5-Br and wherein, for a given compound, R¹, R², R³ and R⁴ correspondto one line of Table A (compounds I.1m.1 to I.1m.81).

Table 12

Compounds of the formula I.1 with a 2-pyridyl radical in which (S)_(n)is 5-OCH₃ and wherein, for a given compound, R¹, R², R³ and R⁴correspond to one line of Table A (compounds I.1n.1 to I.1n.81).

Table 13

Compounds of the formula I.2 with a 4-pyrimidinyl radical in which(S)_(n) is 6-trifluoromethyl and wherein, for a given compound, R¹, R²,R³ and R⁴ correspond to one line of Table A (compounds I.2a.1 toI.2a.81).

Table 14

Compounds of the formula I.2 with a 4-pyrimidinyl radical in which(S)_(n) is 6-CH₃ and wherein, for a given compound, R¹, R², R³ and R⁴correspond to one line of Table A (compounds I.2b.1 to I.2b.81).

Table 15

Compounds of the formula I.2 with a 4-pyrimidinyl radical in which(S)_(n) is 6-OCH₃ and wherein, for a given compound, R¹, R², R³ and R⁴correspond to one line of Table A (compounds I.2c.1 to I.2c.81).

Table 16

Compounds of the formula I.2 with a 4-pyrimidinyl radical in which(S)_(n) is 2-trifluoromethyl and wherein, for a given compound, R¹, R²,R³ and R⁴ correspond to one line of Table A (compounds I.2d.1 toI.2d.81).

Table 17

Compounds of the formula I.2 with a 4-pyrimidinyl radical in which(S)_(n) is 2-CH₃ and wherein, for a given compound, R¹, R², R³ and R⁴correspond to one line of Table A (compounds I.2e.1 to I.2e.81).

Table 18

Compounds of the formula I.2 with a 4-pyrimidinyl radical in which(S)_(n) is 2-OCH₃ and wherein, for a given compound, R¹, R², R³ and R⁴correspond to one line of Table A (compounds I.2f.1 to I.2f.81).

Table 19

Compounds of the formula I.2 with a 5-pyrimidinyl radical in which(S)_(n) is 2-trifluoromethyl and wherein, for a given compound, R¹, R²,R³ and R⁴ correspond to one line of Table A (compounds I.2g.1 toI.2g.81).

Table 20

Compounds of the formula I.2 with a 5-pyrimidinyl radical in which(S)_(n) is 2-CH₃ and wherein, for a given compound, R¹, R², R³ and R⁴correspond to one line of Table A (compounds I.2h.1 to I.2h.81).

Table 21

Compounds of the formula I.2 with a 5-pyrimidinyl radical in which(S)_(n) is 2-OCH₃ and wherein, for a given compound, R¹, R², R³ and R⁴correspond to one line of Table A (compounds I.2i.1 to I.2i.81).

Table 22

Compounds of the formula I.3 with a 2-pyrazinyl radical in which (S)_(n)is 5-trifluoromethyl and wherein, for a given compound, R¹, R², R³ andR⁴ correspond to one line of Table A (compounds I.3a.1 to I.3a.81).

Table 23

Compounds of the formula I.3 with a 2-pyrazinyl radical in which (S)_(n)is CH₃ and wherein, for a given compound, R¹, R², R³ and R⁴ correspondto one line of Table A (compounds I.3b.1 to I.3b.81).

Table 24

Compounds of the formula I.3 with a 2-pyrazinyl radical in which (S)_(n)is OCH₃ and wherein, for a given compound, R¹, R², R³ and R⁴ correspondto one line of Table A (compounds I.3c.1 to I.3c.81).

Table 25

Compounds of the formula I.4, wherein Het is a radical Het-4 and (S)_(n)is hydrogen (n=0) and wherein, for a given compound, R¹, R², R³ and R⁴correspond to one line of Table A (compounds I.4a.1 to I.4a.81).

Table 26

Compounds of the formula I.5, wherein Het is a radical Het-5 and (S)_(n)is hydrogen (n=0) and wherein, for a given compound, R¹, R², R³ and R⁴correspond to one line of Table A (compounds I.5a.1 to I.5a.81).

Table 27

Compounds of the formula I.6, wherein Het is a radical Het-6 and (S)m ishydrogen (m=0) and wherein, for a given compound, R¹, R², R³ and R⁴correspond to one line of Table A (compounds I.6a.1 to I.6a.81).

Table 28

Compounds of the formula I.7, wherein Het is a radical Het-7 and (S)_(n)is hydrogen (n=0) and wherein, for a given compound, R¹, R², R³ and R⁴correspond to one line of Table A (compounds I.7a.1 to I.7a.81).

Table 29

Compounds of the formula I.7 wherein Het=Het-7 in which (S)_(n) is5-chloro and wherein, for a given compound, R¹, R², R³ and R⁴ correspondto one line of Table A (compounds I.7b.1 to I.7b.81).

Table 30

Compounds of the formula I.8 wherein Het=Het-8 in which (S)_(n) ishydrogen (n=0) and wherein, for a given compound, R¹, R², R³ and R⁴correspond to one line of Table A (compounds I.8a.1 to I.8a.81).

Table 31

Compounds of the formula I.8 wherein Het=Het-8 in which (S)_(n) is5-chloro and wherein, for a given compound, R¹, R², R³ and R⁴ correspondto one line of Table A (compounds I.8b.1 to I.8b.81). TABLE A No. R¹ R²R³ R⁴ 1 CH₃ H CH₃ CH₃ 2 C₂H₅ H CH₃ CH₃ 3 C(CH₃)₃ H CH₃ CH₃ 4 CH(CH₃)₂ HCH₃ CH₃ 5 c-C₃H₅ H CH₃ CH₃ 6 c-C₅H₉ H CH₃ CH₃ 7 CH₃ CH₃ CH₃ CH₃ 8 F FCH₃ CH₃ 9 Cl Cl CH₃ CH₃ 10 CH₃ H C₂H₅ CH₃ 11 C₂H₅ H C₂H₅ CH₃ 12 C(CH₃)₃H C₂H₅ CH₃ 13 CH(CH₃)₂ H C₂H₅ CH₃ 14 c-C₃H₅ H C₂H₅ CH₃ 15 c-C₅H₉ H C₂H₅CH₃ 16 CH₃ CH₃ C₂H₅ CH₃ 17 F F C₂H₅ CH₃ 18 Cl Cl C₂H₅ CH₃ 19 CH₃ HCH₂—CH═CH₂ CH₃ 20 C₂H₅ H CH₂—CH═CH₂ CH₃ 21 C(CH₃)₃ H CH₂—CH═CH₂ CH₃ 22CH(CH₃)₂ H CH₂—CH═CH₂ CH₃ 23 c-C₃H₅ H CH₂—CH═CH₂ CH₃ 24 c-C₅H₉ HCH₂—CH═CH₂ CH₃ 25 CH₃ CH₃ CH₂—CH═CH₂ CH₃ 26 F F CH₂—CH═CH₂ CH₃ 27 Cl ClCH₂—CH═CH₂ CH₃ 28 CH₃ H CH₂—C≡CH₂ CH₃ 29 C₂H₅ H CH₂—C≡CH₂ CH₃ 30 C(CH₃)₃H CH₂—C≡CH₂ CH₃ 31 CH(CH₃)₂ H CH₂—C≡CH₂ CH₃ 32 c-C₃H₅ H CH₂—C≡CH₂ CH₃ 33c-C₅H₉ H CH₂—C≡CH₂ CH₃ 34 CH₃ CH₃ CH₂—C≡CH₂ CH₃ 35 F F CH₂—C≡CH₂ CH₃ 36Cl Cl CH₂—C≡CH₂ CH₃ 37 CH₃ H CH₃ CHF₂ 38 C₂H₅ H CH₃ CHF₂ 39 C(CH₃)₃ HCH₃ CHF₂ 40 CH(CH₃)₂ H CH₃ CHF₂ 41 c-C₃H₅ H CH₃ CHF₂ 42 c-C₅H₉ H CH₃CHF₂ 43 CH₃ CH₃ CH₃ CHF₂ 44 F F CH₃ CHF₂ 45 Cl Cl CH₃ CHF₂ 46 CH₃ H C₂H₅CHF₂ 47 C₂H₅ H C₂H₅ CHF₂ 48 C(CH₃)₃ H C₂H₅ CHF₂ 49 CH(CH₃)₂ H C₂H₅ CHF₂50 c-C₃H₅ H C₂H₅ CHF₂ 51 c-C₅H₉ H C₂H₅ CHF₂ 52 CH₃ CH₃ C₂H₅ CHF₂ 53 F FC₂H₅ CHF₂ 54 Cl Cl C₂H₅ CHF₂ 55 CH₃ H CH₂—CH═CH₂ CHF₂ 56 C₂H₅ HCH₂—CH═CH₂ CHF₂ 57 C(CH₃)₃ H CH₂—CH═CH₂ CHF₃ 58 CH(CH₃)₂ H CH₂—CH═CH₂CHF₂ 59 c-C₃H₅ H CH₂—CH═CH₂ CHF₂ 60 c-C₅H₉ H CH₂—CH═CH₂ CHF₂ 61 CH₃ CH₃CH₂—CH═CH₂ CHF₂ 62 F F CH₂—CH═CH₂ CHF₂ 63 Cl Cl CH₂—CH═CH₂ CHF₂ 64 CH₃ HCH₂—C≡CH₂ CHF₂ 65 C₂H₅ H CH₂—C≡CH₂ CHF₂ 66 C(CH₃)₃ H CH₂—C≡CH₂ CHF₂ 67CH(CH₃)₂ H CH₂—C≡CH₂ CHF₂ 68 c-C₃H₅ H CH₂—C≡CH₂ CHF₂ 69 c-C₅H₉ HCH₂—C≡CH₂ CHF₂ 70 CH₃ CH₃ CH₂—C≡CH₂ CHF₂ 71 F F CH₂—C≡CH₂ CHF₂ 72 Cl ClCH₂—C≡CH₂ CHF₂ 73 CH₃ H CH₂—CF₃ CH₃ 74 C₂H₅ H CH₂—CF₃ CH₃ 75 C(CH₃)₃ HCH₂—CF₃ CH₃ 76 CH(CH₃)₂ H CH₂—CF₃ CH₃ 77 c-C₃H₅ H CH₂—CF₃ CH₃ 78 c-C₅H₉H CH₂—CF₃ CH₃ 79 CH₃ CH₃ CH₂—CF₃ CH₃ 80 F F CH₂—CF₃ CH₃ 81 Cl Cl CH₂—CF₃CH₃In Table A, c- is cyclo.

In principle, phenethylacrylamides of the formula I can be preparedanalogously to the prior-art methods mentioned at the outset for thepreparation of phenethylamides and in accordance with the processesillustrated hereinbelow in greater detail.

Moreover, phenethylacrylamides of the formula I wherein R² is hydrogenand R¹ is hydrogen or a radical other than hydrogen, for exampleC₁-C₄-alkyl, C₃-C₈-cycloalkyl or C₁-C₄-haloalkyl, and Het, R³ and R⁴have the abovementioned meanings, can be prepared in accordance with thefollowing process:

-   -   a) reaction of a phenethylamide of the formula II        in which the substituents R¹, R³ and R⁴ have the abovementioned        meanings, with a trialkylstannane (R^(a))₃SnH, wherein R^(a) is        alkyl having preferably 1 to 4 carbon atoms, resulting in a        compound of the formula III        wherein the substituents R^(a), R¹, R³ and R⁴ have the        abovementioned meanings, and    -   b) reaction of the compound III obtained in step a) with a        compound Het-Hal, wherein Hal is bromine or iodine and Het is        one of the above-defined, substituted or unsubstituted aromatic        heterocycle, in the presence of catalytically active amounts of        a transition metal compound of a group VIII metal, in particular        of a palladium(0) and/or a palladium(II) compound.

Step a) is carried out in a manner known per se as described inSynthetic Communications 23(2), 143-152 (1993) and Tetrahedron 48(40),8801-8824 (1992).

Step b) is carried out in a manner known per se under the conditionswhich are customary for a Stille coupling (re. Stille reaction, see: D.Milstein, J. K. Stille, J. Am. Chem. Soc. 1978, 100, pp.3636-3638; V.Farina et al. Org. R^(e) act. 1997, 50, 1-652; J. K. Stille, Angew.Chem. Int. Ed. Engl. 1986, 25, 508).

Preferred as catalysts are palladium(0) and/or palladium(II) compounds,in particular those which have at least one phosphine or nitrile ligand.Examples of phosphine ligands are triarylphosphines such astriphenylphosphine (=PPh₃) and tri(o-tolyl)phosphine (=P(o-tolyl)₃), butalso trialkylphosphines and tricycloalkylphosphines such astricyclohexylphosphine. Examples of nitrile ligands are, in particular,arylnitriles such as benzonitrile. Examples of especially preferredcatalysts are palladium(0)tetrakis(triarylphosphine) such as Pd[PPh₃]₄,Pd[P(o-tolyl)₃]₄ or a dichloropalladium(II)bis(triarylphosphine) such asPdCl₂(PPh₃)₂. The amounts required for effective catalysis are usuallyin the range of from 0.5 to 10 mol %, preferably 1 to 5 mol %, based onthe compound which is present in a substoichiometric amount, for examplethe organotin compound III. The addition of catalytically active amountsof Cu(I) salts such as Cu(I)I in amounts of from 0.5 to 10 mol %,preferably 1 to 5 mol %, based on the compound, for example theorganotin compound III, which is present in a substoichiometric amountis advantageous.

The temperature required for the reaction in step b) is, as a rule, inthe range of from 0 to 140° C., preferably in the range of from 20 to80° C.

Usually, the compound III and Het-Hal will be employed in thestoichiometrically required amounts, Het-Hal frequently being used in anexcess in order to improve the yield. In particular, the molar ratio ofcompound III to Het-Hal is in the range of from 1:0.95 to 1:1.2 andespecially preferably in the range of from 1:0.99 to 1:1.1.

Step b) is usually carried out in an organic solvent, aprotic solventsgenerally being preferred. Particularly suitable are aprotic polarsolvents such as dimethylformamide, dimethyl sulfoxide,N-methylpyrrolidone, tetrahydrofuran, dioxane and aromatic hydrocarbonssuch as toluene and mixtures of these solvents.

The heteroaryl halides Het-Hal which are employed in step b) are knownor can be prepared by conventional methods (see JP 56115776, DE2820032-A1, WO 95/31439-A1).

Similarly, phenethylacrylamides of the formula I where R²═H, wherein R¹is hydrogen or a radical other than hydrogen, for example C₁-C₄-alkyl,C₃-C₈-cycloalkyl or C₁-C₄-haloalkyl, and Het, R³ and R⁴ have theabovementioned meanings are successfully prepared by the followingmethod:

-   -   a′) reaction of a compound of the formula II with at least        stoichiometric amounts of iodine, resulting in a compound of the        formula IV        wherein the substituents R¹, R³ and R⁴ have the abovementioned        meanings, and    -   b′) reaction of the compound IV obtained in step a′) with a        stannane of the formula (R^(a))₃Sn-Het, wherein Het has the        meaning stated in claim 1, in the presence of catalytically        active amounts of a transition metal compound of a group VIII        metal, in particular a palladium(0) and/or a palladium(II)        compound, for example a palladiumtetrakis(triarylphosphine) such        as Pd[PPh₃]₄ or a dichloropalladium(II)bis(triarylphosphine)        such as PdCl₂(PPh₃)₂.

The preparation of the compound IV from the compound II is carried outin a manner known per se by reacting II with elemental iodine asdescribed in Synthetic Communications, 23(2), 143-152 (1993);Tetrahedron Letters 33 (31) 4495-98 (1992) and Tetrahedron 48 (40),8801-8824 (1992).

Coupling of the iodine compound IV with the heterocyclic stannanesHet-Sn(R^(a))₃ is carried out in a manner known per se under theconditions of a Stille coupling, for example under the reactionconditions described for step b).

The heterocyclic stannanes are commercially available in some cases orcan be prepared by customary methods of metallo-organic chemistry, forexample by reacting Grignard compounds Het-Mg—X (X═Cl, Br or I) ororganolithium compounds Het-Li with halotrialkylstannanes Hal-Sn(R^(a))₃(Hal=Cl, Br): see, for example, Synlett (9), 916 (1996); J. Am. Chem.Soc. 106, 4833 (1984); Tetrahedron Letters 39(47), 8643-44 (1998);Synthesis (5), 779-82 (1999); and J. Chem. Soc. B, p. 465 (1968). TheGrignard compounds and the lithium compounds, in turn, can be obtainedin the known manner from the corresponding halogen-substitutedheterocycle Het-Hal (see, for example, Tetrahedron 42(14), 3981-86(1986); Tetrahedron Letters 31(32), 4625-26 (1990); DE-A 3823979; and M.Schlosser, Organometallics in Synthesis, Wiley-Verlag (1994), p. 55ffand references cited therein).

Analogously, steps a) and b), or a′) and b′), respectively, can becarried out starting from phenethylamides of the formula II″

where, in formula II″, the substituents R¹ and R⁴ have theabovementioned meanings and R³″ is hydrogen or an OH protecting group.In this manner, the phenethylacrylamides of the formula I′

are obtained, in which R²═H, wherein R¹, Het and R⁴ have theabovementioned meanings and R³′ is hydrogen or an OH protecting group.

The compounds I′ can, if appropriate after removal of the protectinggroup, be reacted with a compound of the formula R³—Y, wherein R³ hasthe abovementioned meaning and Y is a nucleophilically displaceableleaving group. In this manner, the corresponding phenethylacrylamide ofthe formula I where R²=hydrogen is obtained.

Examples of nucleophilically displaceable leaving groups Y are halogen,in particular chlorine, bromine or iodine, tosylate, methylsulfonate,triflate, acetate and the like.

Examples of OH protecting groups are tetrahydropyran-2-yl, BOC,trialkylsilyl and alkoxyalkyl such as MOM and MEM. They are introducedand removed successfully by methods known from the literature (see, forexample, B. P. J. Kocienski, Protecting Groups, Georg Thieme Verlag2000, pp. 22-94).

The reaction of phenethylacrylamides of the formula I′ wherein R³′ ishydrogen with the compounds R³-Y is carried out in a manner known per seby processes known from the literature (see, for example, B. J. March,Advanced Organic Synthesis, 3rd ed. John Wiley pp. 342-343 andreferences cited therein, and WO 98/38160).

To this end, the compound I′ wherein R³′═H is reacted with preferably atleast stoichiometric amounts of the compound R³—Y, or an excess, forexample up to 10 mol, per mole of compound I′. The reaction ispreferably carried out in an organic solvent, preferably in the presenceof an auxiliary base. Examples of suitable auxiliary bases are alkalimetal carbonates and alkali metal hydrogen carbonates, for examplesodium carbonate, potassium carbonate, sodium hydrogen carbonate orpotassium hydrogen carbonate, tertiary amine, for example triethylamine,pyridine, DBN or DBU, alkali metal alkoxides such as sodium methoxide,sodium ethoxide, sodium-tert-butoxide, the corresponding potassiumalkoxides, and alkali metal hydrides such as sodium hydride. Theauxiliary base is preferably employed in at least equimolar amountsbased on the compound I′, in particular in an amount of from 1.1 to 10mol per mole of compound I′. Solvents which are suitable are, inprinciple, all those which are suitable for nucleophilic substitutionreactions (S_(N) reactions), for example highly polar aprotic solventssuch as acetonitrile, dimethylformamide, dimethyl sulfoxide,N-methylpyrrolidone, tetramethylurea, aprotic polar solvents of mediumpolarity such as dioxane, tetrahydrofuran, halogenated hydrocarbons suchas dichloromethane, dichloroethane, alcoholic solvents such as methanol,ethanol, n- and isopropanol, n-butanol, isobutanol, and furthermorewater and mixtures of the above solvents. In some cases it may beadvantageous to use phase transfer catalysts, for example crown ethersor quaternary ammonium salts. Preferred solvents are aprotic and highlypolar (polar-aprotic). The temperatures required for the reaction are inthe range of from −20 to +100° C., preferably in the range of from 10 to+80° C.

Analogously, the reaction with compounds R³—Y may also be used for thepreparation of other phenethylacrylamides of the formula I in which R²is a radical other than hydrogen. The phenethylacrylamides of theformula I′, being important intermediates for the preparation ofphenethylacrylamides I, are therefore likewise subject matter of thepresent invention.

The phenethylamides of the formula II which are employed as startingmaterials can be prepared in the manner known per se [cf. Houben-Weyl,Methoden der Organischen Chemie [Methods in organic chemistry], Vol. E5,p. 941-972, Georg Thieme Verlag Stuttgart and New York 1985; see alsoTetrahedron 55(46), 13159-70 (1999)] by reacting phenethylamines of theformula VI with propiolic acid compounds of the formula V, ifappropriate in the presence of suitable amidation catalysts, auxiliarybases and/or dehydrating agents, following the method shown in scheme 1:

Propiolic acids of the formula V are either commercially available orcan be prepared in the manner known per se (see Synthesis, p. 72 (1981),Synthesis 498-499 (1987)).

In scheme 1, R¹ and R⁴ have the abovementioned meanings. R³′ has themeanings mentioned for R³ and can also be an OH protecting group orhydrogen. Z is a nucleophilically displaceable leaving group, forexample OH, halogen, in particular chlorine.

If Z is OH, the reaction is preferably carried out in the presence ofdehydrating agents, for example in the presence of carbodiimides such asdicyclohexylcarbodiimide, or diimidazolylcarbonyl, for exampleanalogously to the methods described in Houben-Weyl, Vol. E5, p. 941-972(1985).

As an alternative, the carboxylic acids of the formula V{Z=OH} can,before the amidation, first be activated with VI, for example byconversion into acid halides, in particular into acid chlorides of theformula V{Z=Cl}, analogously to the conditions described in WO 01/95721.

Chlorinating agents which are suitable in this reaction are thecustomary inorganic and organic chlorinating agents, for example thionylchloride, oxalyl chloride, alkyl chloroformate such as ethylchloroformate and isobutyl chloroformate, phosphorus trichloride,phosphorus pentachloride, phosphorus oxychloride,triphenylphosphine/CCl₄, preferably thionyl chloride.

In general, the chlorinating agents are employed in at least equimolaramounts. It may be advantageous for the yield to employ them in anexcess of up to 10 mol per mole of IV, preferably up to 5 mol, inparticular up to 3 mol.

The chlorination of carboxylic acids V{X═OH} is usually carried out attemperatures in the range of from −20° C. to 100° C., preferably from−10° C. to 80° C., in an inert organic solvent [cf. organikum [organicchemistry], 16th Ed., p. 423 et seq., VEB Deutscher Verlag derWissenschaften, Berlin 1985].

The chlorination is usually carried out in a solvent or diluent.Suitable solvents are aliphatic hydrocarbons such as pentane, hexane,cyclohexane and petroleum ether, aromatic hydrocarbons such as toluene,o-, m- and p-xylene, halogenated hydrocarbons such as methylenechloride, chloroform and chlorobenzene, ethers such as diethyl ether,diisopropyl ether, tert-butyl methyl ether, dioxane, anisole andtetrahydrofuran, nitriles such as acetonitrile and propionitrile,ketones such as acetone, methyl ethyl ketone, diethyl ketone andtert-butyl methyl ketone, and dimethyl sulfoxide, dimethylformamide anddimethylacetamide, especially preferably acetonitrile, toluene andtetrahydrofuran. Mixtures of the above may also be used. The liquidchlorinating agent may also act as the solvent.

This reaction is usually carried out at temperatures of from 0° C. 40 to80° C., preferably 20° C. to 40° C., in an inert organic solvent in thepresence of a base [cf. Organikum, 16th Ed., p. 412 et seq., VEBDeutscher Verlag der Wissenschaften, Berlin 1985].

The resulting acid chloride is subsequently reacted with thephenethylamine VI. As a rule, the reaction is carried out in a solventor diluent in the presence of an auxiliary base to scavenge the hydrogenhalide formed during the reaction. Suitable solvents are ethers such asdiethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane,anisole and THF, nitriles such as acetonitrile and propionitrile, anddimethyl sulfoxide, dimethylformamide and dimethylacetamide, especiallypreferably diethyl ether and tetrahydrofuran. Mixtures of these may alsobe used.

Bases which are generally suitable are inorganic compounds such asalkali metal carbonates and alkaline earth metal carbonates such aslithium carbonate, potassium carbonate and calcium carbonate, and alkalimetal hydrogen carbonates such as sodium hydrogen carbonate, furthermoreorganic bases, for example tertiary amines such as trimethylamine,triethylamine, triisopropylethylamine and N-methylpiperidine, pyridine,substituted pyridines such as collidine, lutidine and4-dimethylaminopyridine, and bicyclic amines such as DBN or DBU.Triethylamine and pyridine are especially preferred.

In general, the bases are employed in catalytic amounts, but they mayalso be used in equimolar amounts, in excess or, if appropriate, assolvents.

In general, the starting materials are reacted with each other inequimolar amounts. It may be advantageous for the yields to employ VI inan excess based on V.

As an alternative, phenethylacrylamides of the formula I (and, likewise,phenethylamides of the formula I′) can be prepared in accordance withthe sequence shown in scheme 2 by reacting acrylic acid compounds VIIwith phenethylamines VI.

In scheme 2, R¹, R² and R⁴ have the abovementioned meanings. R³′ has themeanings mentioned for R³ and can also be an OH protecting group orhydrogen. X is preferably OH or halogen, in particular chlorine. Thereaction described in scheme 2 can be carried out analogously to thereaction described in WO 91/95721 for 2-phenylacrylic compounds. Asregards the reaction of the acrylic acid compound VII with thephenethylamine VI, what has been said for the amidation of the propiolicacid compounds V with the phenylamines VI also applies here.

Acrylic acid compounds of the formula VII are known per se or can beprepared by customary methods, in particular by Wittig olefination ofα-ketoesters VIII. Thus, compounds VII in which R¹ and R² are identicaland are Cl, F and CH₃ can be synthesized, for example, starting fromα-ketoesters of the formula VIII in which R is C₁-C₄-alkyl, proceedingas described hereinbelow. The methods required for this purpose areanalogous to the methods described in WO 91/95721 for the conversion ofphenyl-substituted α-ketoesters into 2-arylacrylic acid compounds, sothat reference is made to this publication with regard to furtherdetails.

Acrylic acid compounds VII in which R¹ and R² are chlorine can beprepared for example by reacting α-ketoesters of the formula VIII withtriphenylphosphine (PPh₃) and CCl₄ to give acrylic esters of the formulaVIIa (see also scheme 3). This reaction is usually carried out attemperatures of from 10° C. to 120° C., preferably from 20° C. to 80°C., in an inert organic solvent [cf. Tetrahedron Lett., p. 3003 et seq.,1988; see also WO 91/95721].

Suitable solvents are aromatic hydrocarbons such as toluene, o-, m- andp-xylene, ethers such as diethyl ether, diisopropyl ether, tert-butylmethyl ether, dioxane, anisole, tetrahydrofuran (THF), ethylene glycoldimethyl ether, diethylene glycol dimethyl ether and 1,2-diethoxyethane,nitriles such as acetonitrile and propionitrile, and also dimethylsulfoxide, dimethylformamide and dimethylacetamide, especiallypreferably THF and diethylene glycol dimethyl ether. Mixtures of thesemay also be used.

In general, the starting materials are reacted with each other inequimolar amounts. It may be advantageous for the yield to employ CCl₄and PPh₃ in an excess based on the α-ketoester VIII.

Compounds in which R¹ and R² are fluorine can be prepared for example byreacting α-ketoesters of the formula VIII withdiphenyl-1,1-difluoromethylphoshine of the formula IX in which Ph isphenyl to give acrylic esters of the formula VIIb (see scheme 4). Thisreaction is usually carried out at temperatures of from −70° C. to +80°C., preferably 0° C. to 20° C., in an inert organic solvent in thepresence of a base [cf. Tetrahedron Lett., p. 5571 et seq., 1990, seealso WO 91/95721].

As an alternative, compounds in which R¹ and R² are fluorine can also beobtained by reacting α-ketoesters of the formula VIII withsodium-2-chloro-2,2-difluoracetate, of the formula X, andtriphenylphosphine (PPh₃) to give acrylic esters of the formula VIIb(see scheme 5). This reaction is usually carried out at temperatures offrom 20° C. to 180° C., preferably from 60° C. to 180° C., in an inertorganic solvent [cf. Org. Synth. Vol. V, p. 949 et seq. (1973), see alsoWO 91/95721-A2].

Suitable solvents are ethers such as diethyl ether, diisopropyl ether,tert-butyl methyl ether, dioxane, anisole and tetrahydrofuran,especially preferably diethyl ether and tetrahydrofuran. Mixtures ofthese may also be used.

Suitable bases are, generally, inorganic compounds such as alkali metalhydride and alkaline earth metal hydride, such as lithium hydride,sodium hydride, potassium hydride and calcium hydride, alkali metalamides such as lithium amide, sodium amide and potassium amide,organometal compounds, in particular alkali metal alkyls such asmethyllithium, butyllithium, lithiumdiisopropylamine (LDA) andphenyllithium. Butyllithium and LDA are particularly preferred.

In general, the bases are employed in catalytic amounts, but they mayalso be used in equimolar amounts, in excess or, if appropriate, as thesolvent.

In general, the starting materials are reacted with each other inequimolar amounts. It may be advantageous for the yield to employ IX inan excess based on VIII.

Examples of suitable solvents are aromatic hydrocarbons such as toluene,o-, m- and p-xylene, ethers such as diethyl ether, diisopropyl ether,tert-butyl methyl ether, dioxane, anisole, tetrahydrofuran (THF),ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and1,2-diethoxyethane, nitriles such as acetonitrile and propionitrile, anddimethyl sulfoxide, dimethylformamide and dimethylacetamide, especiallypreferably THF and diethylene glycol dimethyl ether. Mixtures of thesemay also be used.

In general, the starting materials are reacted with each other inequimolar amounts. It may be advantageous for the yield to employ X inan excess based on VIII.

Compounds in which R¹ and R² are methyl can be prepared for example byreacting α-ketoesters of the formula VIII with an isopropylphosphoniumhalide of the formula XI following the principles of a Wittig reaction(see scheme 6). Preferred among the phosphonium halides of the formulaXI are the iodides and the bromides.

In the above reaction scheme, {circle over (P)} in the formula XI is aphosphoranyl radical such as, for example, triphenylphosphoranyl.

The Wittig reaction is usually carried out at temperatures of from −78°C. to +85° C., preferably −10° C. to +65° C., in an inert organicsolvent in the presence of a base [cf. Can. J. Chem. 1971, p. 2143 etseq.].

Suitable solvents are aromatic hydrocarbons such as toluene, o-, m- andp-xylene, ethers such as diethyl ether, diisopropyl ether, tert-butylmethyl ether, dioxane, anisole and tetrahydrofuran (THF), anddimethylformamide and dimethylacetamide, especially preferably diethylether and THF. Mixtures of these may also be used.

Bases which are generally suitable are inorganic compounds such asalkali metal hydrides and alkaline earth metal hydrides such as lithiumhydride, sodium hydride, potassium hydride and calcium hydride, alkalimetal amides such as lithium amide, sodium amide and potassium amide,organometal compounds, in particular alkali metal alkyls such asmethyllithium, butyllithium and phenyllithium, alkali metal alkoxidesand alkaline earth metal alkoxides such as sodium methoxide, sodiumethoxide, potassium ethoxide, potassium tert-butoxide and dimethoxymagnesium. Sodium hydride and sodium ethoxide are particularlypreferred.

In general, the bases are employed in catalytic amounts, but they mayalso be used in equimolar amounts, in excess or, if appropriate, as thesolvent.

In general, the starting materials are reacted with each other inequimolar amounts. It may be advantageous for the yield to employ thephosphonium halide XI in an excess based on α-ketoester VIII.

Carboxylic esters of the formula VIIa to VIIc {where X═C₁-C₄-alkoxy} inwhich R¹ and R² are identical and are Cl, F and CH₃ can be amidated assuch by reaction with the phenethylamine VI. However, they arepreferably hydrolyzed by customary methods to give the carboxylic acidsof the formula VII {X═OH} [cf. Organikum, 16th Ed., pp. 415 and 622, VEBDeutscher Verlag der Wissenschaften, Berlin 1985]. The hydrolysis isusually carried out at temperatures of from 10° C. to 80° C., preferably20° C. to 60° C., in an inert organic solvent in the presence of a basesuch as alkali metal hydroxides or alkaline earth metal hydroxides, inparticular sodium hydroxide or potassium hydroxide.

Carboxylic acids of the formula VII can be amidated directly withphenethylamines of the formula VI in the above-described manner to givethe compounds of the formula I [cf. Houben-Weyl, Methoden derOrganischen Chemie, Vol. E5, p. 941-972, Georg Thieme Verlag Stuttgartand New York 1985] or via their acid chlorides.

The α-ketoesters VIII which are employed as starting materials aredescribed in the literature in some cases or can be prepared in themanner shown in scheme 7 starting from heterocyclyl acetic esters of theformula XII (see WO 01/95721-A2).

In scheme 7, Het and R have the abovementioned meanings.

The bromination of XII to the α-bromoacetic ester XIII is successfullycarried out for example using N-bromosuccinimide (NBS) or1,3-dibromo-5,5-dimethylhydantoin. The bromination is usually carriedout at temperatures of from 0° C. to 200° C., preferably 20° C. to 110°C., in an inert organic solvent in the presence of a free-radicalinitiator [cf. Synthetic R^(e) agents, Vol. 2, pp. 1-63, Verlag Wiley,New York (1974); J. Heterocyclic Chem. pp. 1431-1436 (1993); Synth.Commun. p. 2803 et seq. (1996); J. Med. Chem. p. 481 et seq. (1981)].

The bromine compounds XIII are subsequently oxidized to giveα-ketoesters VIII. The oxidation is successfully carried out withN-methylmorpholine oxide or p-dimethylaminopyridine oxide and is usuallycarried out at temperatures of from 0° C. to 100° C., preferably 20° C.to 60° C., in dimethyl sulfoxide [cf. Bull. Chem. Soc. Jpn., p. 2221(1981)].

As an alternative, phenylacetic acid esters XII can also be oxidizeddirectly to give α-ketoesters VIII. The oxidation can be carried out forexample with SeO₂ or KMnO₄; it is usually carried out at temperatures offrom 20° C. to 180° C., preferably 20° C. to 120° C., in an inertorganic solvent [cf. Synthesis, p. 915 (1994; Synth Commun., p. 1253(1988); J. Gen. Chem. USSR, Vol. 21, p. 694 et seq. (1951)].

The hetarylacetic esters XII which are required for the preparation ofthe compounds VIII are known from the literature or can be prepared inthe manner shown in scheme 8.

Coupling of the heteroaromatic bromides with the trialkylstannanylaceticester(alkyl preferably n-butyl) is carried out in the manner known perse (for example analogously to Bull. Chem. Soc. Jpn. 58, 3383-84 (1985))under the conditions of a Stille coupling (see also what has been saidfor the coupling of III with Het-Hal). To this end, a compound Het-Hal,preferably a compound Het-Br, is reacted with a trialkylstannanylaceticester in the presence of catalytically active amounts of a Pd catalyst,for example of a palladium[tetrakis(triaryl)phosphine] such as Pd(PPh₃]₄or a palladium(II) compound such as PdCl₂[P(o-tolyl)₃]₂,PdCl₂[P(phenyl)₃]₂ or PdCl₂[Ph-CN]₂. The amounts required for effectivecatalysis are usually in the range of from 0.5 to 10 mol %, preferably 1to 5 mol %, based on the compound which is present in a substoichiomericamount, for example the organotin compound III. The addition ofcatalytic amounts of Cu(I) salts such as Cu(I)I in an amount of from 0.5to 10 mol %, preferably 1 to 5 mol %, based on the compound which ispresent in a substoichiometric amount, for example the organotincompound III, is advantageous.

The molar ratio of trialkylstannanylacetic ester to Het-Hal ispreferably in the range of from 1:0.95 to 1:1.2 and especiallypreferably in the range of from 1:0.99 to 1:1.1.

The reaction is usually carried out in a solvent, preferably in anaprotic polar solvent such as dimethylformamide, dimethyl sulfoxide,N-methylpyrrolidone or tetrahydrofuran.

The temperatures required for the reaction are in the range of from 20to 150° C. The tributylstannanylacetic esters are successfully preparedby the method described in zh. Obsch. Khim. 31, 2026 (1961).

If individual compounds I cannot be obtained via the above-describedroutes, they can be prepared by derivatizing other compounds I.

If the synthesis yields isomer mixtures, separation of the isomers is,however, generally not absolutely necessary since some of the individualisomers can undergo conversion into each other during formulation foruse, or upon use (e.g. when exposed to light, acids or bases).Corresponding conversions can also take place after use, for example inthe case of treatment of plants in the treated plant or in the harmfulfungus or animal pest to be controlled.

The reaction mixtures are worked up in the customary manner, for exampleby mixing with water, separating the phases and, if appropriate,purifying the crude products by chromatography. Some of theintermediates and end products are obtained in the form of colorless orpale brown viscous oils which are freed or purified from volatilecomponents under reduced pressure and at moderately elevatedtemperature. If the intermediates and end products are obtained assolids, they may also be purified by recrystallization or digestion.

The compounds I are suitable as fungicides. They are distinguished by anoutstanding activity against a broad spectrum of phytopathogenic fungi,in particular from the classes of the Ascomycetes, Deuteromycetes,Phycomycetes and Basidiomycetes. Some of them act systemically, and theycan be employed in crop protection as foliar- and soil-actingfungicides.

They are especially important for controlling a large number of fungi ona variety of crop plants such as wheat, rye, barley, oats, rice, maize,grass, bananas, cotton, soya, coffee, sugar cane, grapevines, fruitspecies, ornamentals and vegetables such as cucumbers, beans, tomatoes,potatoes and cucurbits, and on the seeds of these plants.

Specifically, they are suitable for controlling the following plantdiseases:

-   -   Alternaria species on vegetables and fruit,    -   Botrytis cinerea (gray mold) on strawberries, vegetables,        ornamentals and grapevines,    -   Cercospora arachidicola on peanuts,    -   Erysiphe cichoracearum and Sphaerotheca fuliginea on cucurbits,    -   Erysiphe graminis (powdery mildew) on cereals,    -   Fusarium and Verticillium species on various plants,    -   Helminthosporium species on cereals,    -   Mycosphaerella species on bananas and peanuts,    -   Phytophthora infestans on potatoes and tomatoes,    -   Plasmopara viticola on grapevines,    -   Podosphaera leucotricha on apples,    -   Pseudocercosporella herpotrichoides on wheat and barley,    -   Pseudoperonospora species on hops and cucumbers,    -   Puccinia species on cereals,    -   Pyricularia oryzae on rice,    -   Rhizoctonia species on cotton, rice and turf,    -   Septoria nodorum on wheat,    -   Uncinula necator on grapevines,    -   Ustilago species on cereals and sugar cane, and    -   Venturia species (scab) on apples and pears.

Moreover, the compounds I are suitable for controlling harmful fungisuch as Paecilomyces variotii in the protection of materials (eg. wood,paper, paint dispersions, fibers and fabrics) and in the protection ofstored products.

The compounds I are applied by treating the fungi, or the plants, seeds,materials or the soil to be protected against fungal infection, with afungicidally active amount of the active ingredients. Application can beeffected both before and after infection of the materials, plants orseeds by the fungi.

In general, the fungicidal compositions comprise from 0.1 to 95,preferably 0.5 to 90% by weight of active ingredient.

When used in crop protection, the rates of application are from 0.01 to2.0 kg of active ingredient per ha, depending on the nature of thedesired effect.

In the treatment of seed, amounts of active ingredient of from 0.001 to0.1 g, preferably 0.01 to 0.05 g, are generally required per kilogram ofseed.

When used in the protection of materials or stored products, the rate ofapplication of active ingredient depends on the nature of the field ofapplication and on the desired effect. Rates of applicationconventionally used in the protection of materials are, for example,from 0.001 g to 2 kg, preferably 0.005 g to 1 kg, of active ingredientper cubic meter of material treated.

The compounds I can be converted into the customary formulations, eg.solutions, emulsions, suspensions, dusts, powders, pastes and granules.The use form depends on the particular purpose; it is intended to ensurein each case a fine and uniform distribution of the compound accordingto the invention.

The formulations are prepared in a known manner, eg. by extending theactive ingredient with solvents and/or carriers, if desired usingemulsifiers and dispersants, it also being possible to use other organicsolvents as auxiliary solvents if water is used as the diluent.Auxiliaries which are suitable are essentially: solvents such asaromatics (eg. xylene), chlorinated aromatics (eg. chlorobenzenes),paraffins (eg. mineral oil fractions), alcohols (eg. methanol, butanol),ketones (eg. cyclohexanone), amines (eg. ethanolamine,dimethylformamide) and water; carriers such as ground natural minerals(eg. kaolins, clays, talc, chalk) and ground synthetic minerals (eg.highly disperse silica, silicates); emulsifiers such as nonionic andanionic emulsifiers (eg. polyoxyethylene fatty alcohol ethers,alkylsulfonates and arylsulfonates) and dispersants such aslignin-sulfite waste liquors and methylcellulose.

Suitable surfactants are alkali metal, alkaline earth metal and ammoniumsalts of lignosulfonic acid, naphthalenesulfonic acid, phenolsulfonicacid, dibutylnaphthalenesulfonic acid, alkylarylsulfonates, alkylsulfates, alkylsulfonates, fatty alcohol sulfates and fatty acids andtheir alkali metal and alkaline earth metal salts, salts of sulfatedfatty alcohol glycol ether, condensates of sulfonated naphthalene andnaphthalene derivatives with formaldehyde, condensates of naphthalene orof napthalenesulfonic acid with phenol or formaldehyde, polyoxyethyleneoctylphenyl ether, ethoxylated isooctylphenol, octylphenol, nonylphenol,alkylphenyl polyglycol ethers, tributylphenyl polyglycol ether,alkylaryl polyether alcohols, isotridecyl alcohol, fattyalcohol/ethylene oxide condensates, ethoxylated castor oil,polyoxyethylene alkyl ethers, ethoxylated polyoxypropylene, laurylalcohol polyglycol ether acetal, sorbitol esters, lignin-sulfite wasteliquors and methylcellulose.

Substances which are suitable for the preparation of directly sprayablesolutions, emulsions, pastes or oil dispersions are mineral oilfractions of medium to high boiling point, such as kerosene or dieseloil, furthermore coal tar oils and oils of vegetable or animal origin,aliphatic, cyclic and aromatic hydrocarbons, eg. benzene, toluene,xylene, paraffin, tetrahydronaphthalene, alkylated naphthalenes or theirderivatives, methanol, ethanol, propanol, butanol, chloroform, carbontetrachloride, cyclohexanol, cyclohexanone, chlorobenzene, isophorone,strongly polar solvents, eg. dimethylformamide, dimethyl sulfoxide,N-methylpyrrolidone and water.

Powders, materials for spreading and dusts can be prepared by mixing orconcomitantly grinding the active substances with a solid carrier.

Granules, eg. coated granules, impregnated granules and homogeneousgranules, can be prepared by binding the active ingredients to solidcarriers. Examples of solid carriers are mineral earths, such assilicas, silica gels, silicates, talc, kaolin, attaclay, limestone,lime, chalk, bole, loess, clay, dolomite, diatomaceous earth, calciumsulfate, magnesium sulfate, magnesium oxide, ground synthetic materials,fertilizers, eg. ammonium sulfate, ammonium phosphate, ammonium nitrate,ureas, and products of vegetable origin, such as cereal meal, tree barkmeal, wood meal and nutshell meal, cellulose powders and other solidcarriers.

In general, the formulations comprise from 0.01 to 95% by weight,preferably from 0.1 to 90% by weight, of the active ingredient. Theactive ingredients are employed in a purity of from 90% to 100%,preferably 95% to 100% (according to NMR spectrum).

The following are examples of formulations:

-   -   I. 5 parts by weight of a compound according to the invention        are mixed intimately with 95 parts by weight of finely divided        kaolin. This gives a dust which comprises 5% by weight of the        active ingredient.    -   II. 30 parts by weight of a compound according to the invention        are mixed intimately with a mixture of 92 parts by weight of        pulverulent silica gel and 8 parts by weight of paraffin oil        which had been sprayed onto the surface of this silica gel. This        gives a formulation of the active ingredient with good adhesion        properties (comprises 23% by weight of active ingredient).    -   III. 10 parts by weight of a compound according to the invention        are dissolved in a mixture composed of 90 parts by weight of        xylene, 6 parts by weight of the adduct of 8 to 10 mol of        ethylene oxide and 1 mol of oleic acid N-monoethanolamide, 2        parts by weight of calcium dodecylbenzenesulfonate and 2 parts        by weight of the adduct of 40 mol of ethylene oxide and 1 mol of        castor oil (comprises 9% by weight of active ingredient).    -   IV. 20 parts by weight of a compound according to the invention        are dissolved in a mixture composed of 60 parts by weight of        cyclohexanone, 30 parts by weight of isobutanol, 5 parts by        weight of the adduct of 7 mol of ethylene oxide and 1 mol of        isooctylphenol and 5 parts by weight of the adduct of 40 mol of        ethylene oxide and 1 mol of castor oil (comprises 16% by weight        of active ingredient).    -   V. 80 parts by weight of a compound according to the invention        are mixed thoroughly with 3 parts by weight of sodium        diisobutylnaphthalene-alpha-sulfonate, 10 parts by weight of the        sodium salt of a lignosulfonic acid from a sulfite waste liquor        and 7 parts by weight of pulverulent silica gel, and the mixture        is ground in a hammer mill (comprises 80% by weight of active        ingredient).    -   VI. 90 parts by weight of a compound according to the invention        are mixed with 10 parts by weight of N-methyl-α-pyrrolidone,        which gives a solution which is suitable for use in the form of        microdrops (comprises 90% by weight of active ingredient).    -   VII. 20 parts by weight of a compound according to the invention        are dissolved in a mixture composed of 40 parts by weight of        cyclohexanone, 30 parts by weight of isobutanol, 20 parts by        weight of the adduct of 7 mol of ethylene oxide and 1 mol of        isooctylphenol and 10 parts by weight of the adduct of 40 mol of        ethylene oxide and 1 mol of castor oil. Pouring the solution        into 100,000 parts by weight of water and finely distributing it        therein gives an aqueous dispersion which comprises 0.02% by        weight of the active ingredient.    -   VIII. 20 parts by weight of a compound according to the        invention are mixed thoroughly with 3 parts by weight of sodium        diisobutylnaphthalene-α-sulfonate, 17 parts by weight of the        sodium salt of a lignosulfonic acid from a sulfite waste liquor        and 60 parts by weight of pulverulent silica gel, and the        mixture is ground in a hammer mill. Finely distributing the        mixture in 20,000 parts by weight of water gives a spray mixture        which comprises 0.1% by weight of the active ingredient.

The active ingredients can be used as such, in the form of theirformulations or the use forms prepared therefrom, eg. in the form ofdirectly sprayable solutions, powders, suspensions or dispersions,emulsions, oil dispersions, pastes, dusts, materials for spreading, orgranules, by means of spraying, atomizing, dusting, spreading orpouring. The use forms depend entirely on the intended purposes; it isintended to ensure in each case the finest possible distribution of theactive ingredients according to the invention.

Aqueous use forms can be prepared from emulsion concentrates, pastes orwettable powders (sprayable powders, oil dispersions) by adding water.To prepare emulsions, pastes or oil dispersions, the substances, as suchor dissolved in an oil or solvent, can be homogenized in water by meansof wetter, tackifier, dispersant or emulsifier. Alternatively, it ispossible to prepare concentrates composed of active substance, wetter,tackifier, dispersant or emulsifier and, if appropriate, solvent or oil,and such concentrates are suitable for dilution with water.

The active ingredient concentrations in the ready-to-use preparationscan be varied within relatively wide ranges. In general, they are from0.0001 to 10%, preferably from 0.01 to 1%.

The active ingredients may also be used successfully in theultra-low-volume process (ULV), it being possible to apply formulationscomprising over 95% by weight of active ingredient, or even to apply theactive ingredient without additives.

Various types of oils, herbicides, fungicides, other pesticides, orbactericides may be added to the active ingredients, if appropriate justimmediately prior to use (tank mix). These agents can be admixed withthe agents according to the invention in a weight ratio of 1:10 to 10:1.

In the use form as fungicides, the compositions according to theinvention can also be present together with other active ingredients,eg. with herbicides, insecticides, growth regulators, fungicides or elsewith fertilizers. Mixing the compounds I or the compositions comprisingthem in the use form as fungicides with other fungicides frequentlyresults in a broader fungicidal spectrum of action.

The following list of fungicides together with which the compoundsaccording to the invention can be used is intended to illustrate thepossible combinations, but not to impose any limitation:

-   -   sulfur, dithiocarbamates and their derivatives, such as        iron(III) dimethyldithiocarbamate, zinc dimethyldithiocarbamate,        zinc ethylenebisdithiocarbamate, manganese        ethylenebisdithiocarbamate, manganese zinc        ethylenediaminebisdithiocarbamate, tetramethylthiuram disulfide,        ammonia complex of zinc (N,N-ethylenebisdithiocarbamate),        ammonia complex of zinc (N,N′-propylenebisdithiocarbamate), zinc        (N,N′-propylenebisdithiocarbamate),        N,N′-polypropylenebis(thiocarbamoyl)disulfide;    -   nitro derivatives, such as dinitro(1-methylheptyl)phenyl        crotonate, 2-sec-butyl-4,6-dinitrophenyl-3,3-dimethylacrylate,        2-sec-butyl-4,6-dinitrophenylisopropyl carbonate, diisopropyl        5-nitro-isophthalate;    -   heterocyclic substances, such as 2-heptadecyl-2-imidazoline        acetate, 2,4-dichloro-6-(o-chloroanilino)-s-triazine,        O,O-diethyl phthalimidophosphonothioate,        5-amino-1-[bis(dimethylamino)phosphinyl]-3-phenyl-1,2,4-triazole,        2,3-dicyano-1,4-dithioanthraquinone,        2-thio-1,3-dithiolo[4,5-b]quinoxaline, methyl        1-(butylcarbamoyl)-2-benzimidazolecarbamate,        2-methoxycarbonylaminobenzimidazole, 2-(2-furyl)benzimidazole,        2-(4-thiazolyl)benzimidazole,        N-(1,1,2,2-tetrachloroethylthio)tetrahydrophthalimide,        N-tri-chloromethylthiotetrahydrophthalimide,        N-trichloromethylthiophthalimide,    -   N-dichlorofluoromethylthio-N′,N′-dimethyl-N-phenylsulfodiamide,        5-ethoxy-3-trichloromethyl-1,2,3-thiadiazole,        2-thiocyanatomethylthiobenzothiazole,        1,4-dichloro-2,5-dimethoxybenzene,        4-(2-chlorophenylhydrazono)-3-methyl-5-isoxazolone,        pyridine-2-thiol 1-oxide, 8-hydroxyquinoline or its copper salt,        2,3-dihydro-5-carboxanilido-6-methyl-1,4-oxathiine,        2,3-dihydro-5-carboxanilido-6-methyl-1,4-oxathiine 4,4-dioxide,        2-methyl-5,6-dihydro-4H-pyran-3-carboxanilide,        2-methylfuran-3-carboxanilide,        2,5-dimethylfuran-3-carboxanilide,        2,4,5-trimethylfuran-3-carboxanilide,        N-cyclohexyl-2,5-dimethylfuran-3-carboxamide(s),        N-cyclohexyl-N-methoxy-2,5-dimethylfuran-3-carboxamide,        2-methylbenzanilide, 2-iodobenzanilide,        N-formyl-N-morpholine-2,2,2-trichloroethyl acetal,        piperazine-1,4-diylbis-1-(2,2,2-trichloroethyl)formamide,        1-(3,4-dichloroanilino)-1-formylamino-2,2,2-trichloroethane,        2,6-dimethyl-N-tridecylmorpholine or its salts,        2,6-dimethyl-N-cyclododecylmorpholine or its salts,        N-[3-(p-tert-butylphenyl)-2-methylpropyl]-cis-2,6-dimethylmorpholine,        N-[3-(p-tert-butylphenyl)-2-methylpropyl]piperidine,        1-[2-(2,4-dichlorophenyl)-4-ethyl-1,3-dioxolan-2-yl-ethyl]-1H-1,2,4-triazole,        1-[2-(2,4-dichlorophenyl)-4-n-propyl-1,3-dioxolan-2-yl-ethyl]-1H-1,2,4-triazole,        N-(n-propyl)-N-(2,4,6-trichlorophenoxyethyl)-N′-imidazolylurea,        1-(4-chlorophenoxy)-3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)-2-butanone,        1-(4-chlorophenoxy)-3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)-2-butanol,        (2RS,3RS)-1-[3-(2-chlorophenyl)-2-(4-fluorophenyl)oxiran-2-ylmethyl]-1H-1,2,4-triazole,        α-(2-chlorophenyl)-α-(4-chlorophenyl)-5-pyrimidinemethanol,        5-butyl-2-dimethylamino-4-hydroxy-6-methylpyrimidine,        bis(p-chlorophenyl)-3-pyridinemethanol,        1,2-bis(3-ethoxycarbonyl-2-thioureido)benzene,        1,2-bis(3-methoxycarbonyl-2-thioureido)benzene,    -   strobilurins such as methyl        E-methoxyimino-[α-(o-tolyloxy)-o-tolyl]acetate, methyl        E-2-{2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]-phenyl}-3-methoxyacrylate,        N-methyl-E-methoxy-imino-[α-(2-phenoxyphenyl)]acetamide,        N-methyl        E-methoxyimino-[α-(2,5-dimethylphenoxy)-o-tolyl]acetamide,    -   anilinopyrimidines such as        N-(4,6-dimethylpyrimidin-2-yl)aniline,        N-[4-methyl-6-(1-propynyl)pyrimidin-2-yl]aniline,        N-[4-methyl-6-cyclopropylpyrimidin-2-yl]aniline,    -   phenylpyrroles such as        4-(2,2-difluoro-1,3-benzodioxol-4-yl)pyrrole-3-carbonitrile,    -   cinnamamides such as        3-(4-chlorophenyl)-3-(3,4-dimethoxy-phenyl)acryloylmorpholine,    -   and a variety of fungicides such as dodecylguanidine acetate,        3-[3-(3,5-dimethyl-2-oxycyclohexyl)-2-hydroxyethyl]glutarimide,        hexachlorobenzene, methyl        N-(2,6-dimethylphenyl)-N-(2-furoyl)-DL-alaninate,        DL-N-(2,6-dimethylphenyl)-N-(2′-methoxyacetyl)-alanine methyl        ester,        N-(2,6-dimethylphenyl)-N-chloroacetyl-D,L-2-amino-butyrolactone,        DL-N-(2,6-dimethylphenyl)-N-(phenylacetyl)-alanine methyl ester,        5-methyl-5-vinyl-3-(3,5-dichlorophenyl)-2,4-dioxo-1,3-oxazolidine,        3-(3,5-dichlorophenyl)5-methyl-5-methoxymethyl-1,3-oxazolidine-2,4-dione,        3-(3,5-dichlorophenyl)-1-isopropylcarbamoylhydantoin,        N-(3,5-dichlorophenyl)-1,2-dimethylcyclopropane-1,2-dicarboximide,        2-cyano-[N-(ethylaminocarbonyl)-2-methoximino]acetamide,        1-[2-(2,4-dichlorophenyl)pentyl]-1H-1,2,4-triazole,        2,4-difluoro-α-(1H-1,2,4-triazolyl-1-methyl)benzhydryl alcohol,        N-(3-chloro-2,6-dinitro-4-trifluoromethylphenyl)-5-trifluoromethyl-3-chloro-2-aminopyridine,        1-((bis(4-fluorophenyl)methylsilyl)methyl)-1H-1,2,4-triazole.

PREPARATION EXAMPLES

With due modification of the starting compounds, the procedures given inthe synthesis examples hereinbelow were used to obtain further compoundsI. The resulting compounds, together with physical data, are listed inthe subsequent table.

Example 1(2Z)-N-[2-(3,4-Dimethoxyphenyl)ethyl]-4-methyl-2-[5-(trifluoromethyl)-2-pyridinyl]-2-pentenamide

1.1 5-Isopropyl-2,4-dihydro-3H-pyrazol-3-one (1)

70 g (1.26 mol) of hydrazine hydrate were added dropwise at 10-30° C. to100 g (0.62 mol) of ethyl 2-isobutyrylacetate (=4-methyl-3-oxopentanoicacid ethyl ester) in 60 ml of ethanol. After the exothermic reaction hadsubsided, the mixture was stirred over 16 hours and cooled to −10° C.,and the title compound 1 was filtered off with suction. Yield: 52 g.

¹H NMR (CDCl₃): δ 9.5 (br, 1H); 5.25 (s, 1H); 2.75 (q, 1H); 1.1 (d, 6H).

1.2 4,4-Dibromo-5-isopropyl-2,4-dihydro-3H-pyrazol-3-one (2)

140 g (0.87 mol) of bromine were added dropwise to 52 g (0.41 mol) of5-isopropyl-2,4-dihydro-3H-pyrazol-3-one (1) in 300 ml of glacial aceticacid. The reaction mixture was subsequently poured into ice-water andthe title compound 2 which had precipitated was filtered off withsuction. Yield: 113 g

¹H NMR (CDCl₃): δ 9.5 (br, 1H); 3.0 (q, 1H); 1.35 (d, 6H).

1.3 4-Methyl-2-pentynoic acid (3)

60 g (0.21 mol) of 4,4-dibromo-5-isopropyl-2,4-dihydro-3H-pyrazol-3-one(2) in 150 ml methyl tert-butyl ether were added dropwise at 0° C. to400 ml of 10% strength sodium hydroxide solution and the mixture wasstirred for 3 hours at room temperature. The aqueous phase was separatedoff, brought to pH 2.5 with concentrated hydrochloric acid and extractedwith methyl tert-butyl ether, and the extract was dried. After removalof the solvent, 23.3 g of 4-methyl-2-pentynoic acid (3) were obtained.

¹H NMR (CDCl₃): δ 8.0 (br, OH); 2.7 (q, 1H); 1.2 (d, 6H).

1.4 2-(3,4-Dimethoxyphenyl)ethyl-4-methyl-2-pentynoate (4)

At 0-5° C., 38.2 g (280 mmol) of isobutyl chloroformate and, at 5-15°C., 28.3 g (280 mmol) of N-methylmorpholine were added dropwise to 28.4g (254 mmol) of 4-methyl-2-pentynoic acid (3) in 100 ml of THF. 46 g(254 mmol) of homoveratrylamine were subsequently added dropwise withice-cooling, and stirring was continued for 48 hours at roomtemperature. Thereupon, the reaction mixture was concentrated, theresidue was poured into water/10% strength hydrochloric acid, and theaqueous mixture was extracted with methyl tert-butyl ether. After dryingand concentration, the residue was chromatographed over silica gel usingcyclohexane/methyl tert-butyl ether (3:1), yielding 44 g of compound 4.

¹H NMR (CDCl₃): δ 6.85-6.6 (m, 3H); 5.75 (m, 1H); 3.85 (s, 3H); 3.80 (s,3H), 3.5 (q, 2H).

1.5(2E)-N-[2-(3,4-Dimethoxyphenyl)ethyl]-4-methyl-2-(tributylstannyl)-2-pentenamide(5)

0.8 g of Pd(PPh₃)₄ was added to 47.1 g (170 mmol) of2-(3,4-dimethoxyphenyl)ethyl-4-methyl-2-pentynoate (4) in 200 ml of THF,and 51 g (175 mmol) of tributyltin hydride in 50 ml of tetrahydrofuranwere added dropwise at 15-20° C. Stirring was continued for 16 hours atroom temperature, the mixture was concentrated, and the residue waschromatographed over silica gel using cyclohexane/methyl tert-butylether (3:1). This gave 88.8 g of compound 5 as a viscous oil.

¹H NMR (CDCl₃): δ 6.8-6.7 (m, 3H); 5.4 (d, 1H); 5.2(m, 1H); 3.9 (s, 3H);3.85 (s, 3H).

1.6(2Z)-N-[2-(3,4-Dimethoxyphenyl)ethyl]-4-methyl-2-[5-(trifluoromethyl)-2-pyridinyl]-2-pentenamide(6)

0.5 g (2.21 mmol) of 2-bromo-5-trifluoromethylpyridine, 140 mg Pd(PPh₃)₄and approx. 100 mg of copper(I) iodide were added to 1.28g (2.21 mmol)of(2E)-N-[2-(3,4-dimethoxyphenyl)ethyl]-4-methyl-2-(tributylstannyl)-2-pentenamide(5) in 2 ml of dimethylformamide. The mixture was stirred overnight atroom temperature, poured into water and extracted with methyl tert-butylether. The organic phases were washed with water, dried andconcentrated. The residue was chromatographed over silica gel usingcyclohexane/methyl tert-butyl ether (3:1 to 1:1), yielding 0.5 g of thefinal product 6.

¹H NMR (CDCl₃): δ 8.75 (s, 1H); 7.8 (d, 1H); 7.35 (d, 1H); 4.0 (q, 2H);3.8 (s, 3H).

The compounds of Examples 2 to 23 were prepared analogously. Thecompound of Example 2 was obtained as by-product in the preparation ofExample 3. The physical data of the compounds of Examples 1 to 23 areshown in Table B. As regards the ¹H NMR spectra, only characteristicsignals were stated. All of the chemical shifts are based ontetramethylsilane. s represents singlet, q quartet, t triplet and mhigher-order multiplet. TABLE B

Physical data (m.p. [° C.]; ¹H NMRδ Ex. R¹ R² Het R³ [ppm], GC[min]) 1CH(CH₃)₂ H 5-CF₃-pyri- CH₃ 8.75(s, 1H); din-2-yl 7.8(d, 1H); 7.35(d,1H); 4.0(q, 2H); 3.8(s, 3H) 2 H C₂H₅ pyridin-2-yl C₂H₅ 1.1(t, 3H);1.4(t, 3H); 2.75(t, 2H); 3.2(q, 2H); 3.6(q, 2H); 3.8(s, 3H); 4.0(q, 2H)3 C₂H₅ H 5-methyl-py- C₂H₅ 49-56 ridin-2-yl 4 C₂H₅ H pyridin-2-yl C₂H₅79-80 5 C₂H₅ H 4-methyloxa- C₂H₅ 0.9(t, 3H); 2.3(s, zol-2-yl (s, 3H);2.6(q, 2H); 2.8(t, 2H); 3.7(q, 2H); 3.8(s, 3H) 6 c-C₆H₁₁ H 5-bromopyri-CH₃ 8.5(s, 1H); 7.7(d, din-2-yl 1H); 7.1(d, 1H); 1.6-1.8(m, 5H);1.05-1.4(m, 5H) 7 CH(CH₃)₂ H 5-CF₃-pyri- C₂H₅ 8.75(s, 1H); din-2-yl7.8(d, 1H); 7.35(d, 1H); 4.0(q, 2H); 3.8(s, 3H) 8 c-₃H₅ H 5-bromopyri-CH₃ 8.4(s, 1H); 5.8(s, din-2-yl 1H); 3.9(s, 3H); 3.8(s, 3H); 2.85(t, 2H)9 C(CH₃)₃ H 5-CF₃-pyri- C₂H₅ 1.1(s, 9H); 1.4(t, din-2-yl 3H); 2.75(t,2H); 6.1(m, 1H); 8.75(s, 1H) 10 CH(CH₂CH₃)₂ H 5-CF₃-pyri- CH₃ 2.55(m);2.8(d); din-2-yl 3.75(m); 3.95(d); 6.3(d); 7.35(d); 8.75(s) 11CH(CH₂CH₃)₂ H 5-CH₃-pyri- CH₃ GC: 13.8 din-2-yl 12 C₂H₅ H 5-CF₃-pyri-CH₃ GC: 12.12 din-2-yl 13 C₂H₅ H 5-bromo-pyri- C₂H₅ GC: 13.88 din-2-yl14 C₂H₅ H 5-CF₃-pyri- C₂H₅ GC: 12.30 din-2-yl 15 C₂H₅ H 5-bromo-pyri-CH₃ GC: 14.1 din-2-yl 16 CH(CH₃)₂ H 5-CF₃-pyri- CH₃ GC: 12.07 din-2-yl17 CH(CH₃)₂ H 5-bromo-pyri- CH₃ GC: 13.82 din-2-yl 18 C(CH₃)₃ H5-CF₃-pyri- CH₃ GC: 12.34 din-2-yl 19 C(CH₃)₃ H 5-bromo-pyri- CH₃ GC:14.13 din-2-yl 20 c-C₃H₅ H 5-CF₃-pyri- CH₃ 105-108 din-2-yl 21C(CH₃)₂OCH₃ H 5-bromo-pyri- CH₃ 3.2(s); 3.7(m); din-2-yl 3.85(s);7.2(d); 8.6(s) 22 C(CH₃)CH₂CH₃ H 5-bromo-pyri- CH₃ 2.8(t); 3.7(m);din-2-yl 3.85(d); 6.25(d); 7.75(d); 8.5(s) 23 CH(CH₂CH₃)₂ H5-bromo-pyri- CH₃ 2.6(m); 2.8(d); din-2-yl 3.7(m); 3.95(d); 6.2(d);7.2(d); 7.75(t); 8.5(s)c = cyclo*GC: conditions: column: 10 m; Optima 1, Macherey & Nagel; programm:80/0/15/280/16/293

Examples of the action against harmful fungi

The fungicidal action of the compounds of the formula I is demonstratedby the following experiments:

The active ingredients were prepared separately or jointly as a 10%emulsion in a mixture of 85% by weight cyclohexanone and 5% by weightWettol® EM (nonionic emulsifier based on ethoxylated castor oil) in theform of a stock solution and diluted with water to give the desiredconcentration.

Use Example 1 Activity Against Gray Mold on Capsicum Leaves Caused byBotrytis cinerea

Capsicum seedlings cv. “Neusiedler Ideal Elite” were allowed to develop4-5 leaves properly and were then sprayed to runoff point with anaqueous suspension made with the above stock solution. The next day, thetreated plants were inoculated with a spore suspension of Botrytiscinerea which contained 1.7×10⁶ spores/ml in a 2% strength aqueousBiomalz solution. The test plants were subsequently placed into acontrolled-environment cabinet at 22-24° C. and high atmospherichumidity. After 5 days, it was possible to visually determine the extentof the fungal infection on the leaves in %.

In this study, the plants treated with 250 ppm of the respective activeingredient of Examples 2, 4 or 5 of Table B showed a disease level ofnot more than 5% or no disease at all, while the untreated plants showeda disease level of 90%.

Use Example 2 Activity Against Tomato Blight Caused by Phytophthorainfestans

Leaves of potted plants cv. “GroBe Fleischtomate St. Pierre” weresprayed to runoff point with an aqueous suspension made with the abovestock solution. The next day, the leaves were inoculated with a coldaqueous zoospore suspension of Phytophthora infestans at a concentrationof 0.25×10⁶ spores/ml. The plants were subsequently placed into achamber with 100% atmospheric humidity at temperatures of between 18 and20° C. After 6 days, the blight had developed to such an extent on theuntreated, but inoculated, control plants that it was possible tovisually determine the disease level in %.

In this study, the plants which had been treated with 250 ppm of therespective active ingredient of Example 2 or 4 of Table B showed adisease level of not more than 15% and those which had been treated with250 ppm of the active ingredients of Example 5, 7, 8 or 9 weredisease-free, while the disease level of the untreated plants was 100%.

Use Example 3 Activity Against Downy Mildew of Grapevine Caused byPlasmopara viticola

Leaves of potted grapevines cv. “Müller-Thurgau” were sprayed to runoffpoint with an aqueous suspension prepared with the above stock solution.The next day, the undersides of the leaves were inoculated with anaqueous zoospore suspension of Plasmopara viticola. Thereafter, thegrapevines were first placed for 48 hours into a chamber at 24° C. and100% atmospheric humidity and subsequently for 5 days in a greenhouse attemperatures of between 20 and 30° C. After this time, the plants werereturned for 16 hours into a humid chamber to accelerate the eruption ofsporangiophores. The extent to which the disease had developed on theundersides of the leaves was then determined visually.

In this study, the plants which had been treated with 250 ppm of therespective active ingredient of Example 7, 8 or 9 of Table B showed adisease level of not more than 5% or were free from disease, while theuntreated plants showed a disease level of 80%.

1. Phenethylacrylamides of the formula I

in which the substituents R¹, R², R³ and R⁴ have the following meanings: R¹ is halogen, C₁-C₄-alkyl, C₁-C₄-alkoxy, C₃-C₁₀-cycloalkyl, C₁-C₄-haloalkoxy or C₁-C₄-haloalkyl; R² is hydrogen; R³ is C₁-C₄-alkyl, C₁-C₄-haloalkyl, propargyl, C₃-C₄-alkenyl or —H₂C—C≡C—C(R^(a), R^(a))—R^(c), where R^(a), R^(b) independently of one another are hydrogen or methyl and R^(c) is hydrogen or C₁-C₄-alkyl; R⁴ is methyl or C₁-haloalkyl; and Het is a 5- or 6-membered heteroaromatic ring which may contain a fused 5- or 6-membered carbocycle and which is selected from among heteroaromatic rings containing 1, 2, 3 or 4 nitrogen atoms as ring members, heteroaromatic rings which contain 1 or 2 nitrogen atoms and 1 or 2 further heteroatoms selected from among oxygen or sulfur as ring members, and heteroaromatic rings which have 1 or 2 heteroatoms selected from among oxygen and sulfur as ring members, Het being unsubstituted or it being possible for Het to contain 1, 2 or 3 substituents S selected from among halogen, C₁-C₄-alkyl, C₁-C₄-haloalkoxy, C₁-C₄-haloalkyl and C₁-C₄-alkoxy.
 2. A phenethylacrylamide of the formula I as claimed in claim 1, wherein R¹ is C₁-C₄-alkyl or C₃-C₆-cycloalkyl, in particular ethyl, isopropyl, tert-butyl or cyclopropyl.
 3. A phenethylacrylamide of the formula I as claimed in any of the preceding claims, wherein Het is selected from among pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, thienyl, furanyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl.
 4. A phenethylacrylamide of the formula I as claimed in any of the preceding claims, wherein Het contains one or two substituents S which are bonded to those ring atoms which are not adjacent to the linkage site forming the double bond.
 5. A phenethylacrylamide of the formulae I.1, I.2 and I.3

in which the substituents S, R¹, R², R³ and R⁴ have the abovementioned meanings and n is 1 or 2, and S is not bonded in the ortho position relative to the linkage site.
 6. A process for the preparation of a phenethylacrylamide of the formula I as claimed in any of the preceding claims, wherein R² is hydrogen and R¹ is hydrogen, C₁-C₄-alkyl, C₃-C₈-cycloalkyl or C₁-C₄-haloalkyl, and Het, R³ and R⁴ have the abovementioned meanings, comprising the following steps: a) reaction of a phenethylamide of the formula II,

in which the substituents R¹, R³ and R⁴ have the abovementioned meanings, with a trialkylstannane (R^(a))₃SnH, wherein R^(a) is alkyl resulting in a compound of the formula III

wherein the substituents R^(a), R¹, R³ and R⁴ have the abovementioned meanings, and b) reaction of the compound III obtained in step a) with a compound Het-Hal, wherein Hal is bromine or iodine and Het has the meaning given in claim 1, in the presence of catalytically active amounts of a transition metal compound of a group VIII metal; or a′) reaction of a compound of the formula II with at least stoichiometric amounts of iodine, resulting in a compound of the formula IV

wherein the substituents R¹, R³ and R⁴ have the abovementioned meanings, and b′) reaction of the compound IV obtained in step a′) with a stannane of the formula (R^(a))₃Sn-Het, wherein Het has the meaning stated in claim 1, in the presence of catalytically active amounts of a transition metal compound of a group VIII metal.
 7. A process as claimed in claim 6, additionally comprising the preparation of the phenethylamide of the formula II, wherein a propiolic acid compound of the formula V

wherein R¹ has the abovementioned meaning and Z is halogen or OH, is reacted in a manner known per se with a phenethylamine of the general formula VI

wherein R³ and R⁴ have the abovementioned meanings.
 8. A process for the preparation of a phenethylacrylamide as claimed in claim 1 of the formula I, wherein a phenethylacrylamide of the formula I where R³═H:

wherein Het, R¹, R² and R⁴ have the abovementioned meanings, is reacted with a compound of the formula R³—Y, wherein R³ has the abovementioned meaning and Y is a nucleophilically displaceable leaving group.
 9. A phenethylamide of the formula II′

wherein the substituents R¹ and R⁴ have the abovementioned meanings, R³′ has the meanings stated for R³ or R³′ is hydrogen or an OH protecting group.
 10. A phenethylacrylamide of the formula I′:

wherein Het, R¹, R² and R⁴ have the abovementioned meanings and R³′ is hydrogen or an OH protecting group.
 11. A composition for controlling phytopathogenic harmful fungi comprising a solid or liquid carrier and a compound of the formula I as claimed in any of claims 1 to
 5. 12. A method of controlling phytopathogenic harmful fungi, which comprises treating the fungi or the materials, plants, the soil or seed to be protected from fungal infection with an effective amount of a compound of the formula I as claimed in any of claims 1 to
 5. 